Epstein Barr virus is the cause of infectious mononucleosis and is associated with a number of cancers including Hodgkin's disease and Burkitt's lymphoma. Chronic active Epstein-Barr virus is a rare disease in which persons have persistent organ disease due to the virus that lasts for more than six months. We are studying patients with chronic active Epstein-Barr virus to try to determine the cause of this disease. Patients with the X-linked lymphoproliferative disorder (XLPD) develop fulminant mononucleosis and those who survive have a clinical course that has some features in common with CAEBV. Patients with XLPD have mutations in the SAP protein. Since some patients with CAEBV have been reported to have defects in killing of target cells by their white blood cells, we have focused on proteins, such as interferon alpha and gamma, which are important for white blood cells to kill virus-infected cells. Sequencing of the SAP gene and the interferon gamma receptor gene have not shown any mutations in patients with CAEBV. Current studies are focusing on other proteins that mediate killing of virus-infected cells such as perforin and granzymes. Preliminary experiments have identified novel mutations in both copies of the perforin gene in a patient who died with CAEBV. The patient had a very low level of perforin in his white blood cells compared with healthy blood donors, and he had an abnormal accumulation of a precursor form of perforin.